Lower Activity of CCAAT/Enhancer-Binding Protein and Expression of Cyclin E, but Not Cyclin D1, Activating Protein-1 and p21WAF1, after Partial Hepatectomy in Obstructive Jaundice

doi:10.1006/bbrc.2000.4185

Biochemical and Biophysical Research Communications

Volume 280, Issue 3, 26 January 2001, Pages 640-645

https://doi.org/10.1006/bbrc.2000.4185 Get rights and content

Abstract

CCAAT/enhancer-binding protein (C/EBP)-α stabilizes p21^WAF1, whereas activating protein-1 (AP-1) and C/EBP-β enhance cyclin D1 and cyclin E expression, respectively, during the progress of liver regeneration. In this study, we investigated the differences in the transcription factors and cell cycle regulators between obstructive jaundiced and control rats before and after hepatectomy accompanied with a release of biliary obstruction by internal biliary drainage. The expressions and activities of C/EBP-α and -β were significantly decreased in the jaundiced group concomitant with the significantly lower cyclin E expression after hepatectomy than in the controls. The activities of AP-1, cyclin D1 and p21^WAF1 were not significantly different between the two groups. These results suggest that obstructive jaundice inhibits hepatic expression and activity of C/EBP, resulting in the impaired cyclin E expression that is partly responsible for the cell cycle dysfunction after hepatectomy.

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Cited by (24)

Chapter 6 - Liver regeneration: Mechanisms and clinical relevance
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Predicting liver failure following major hepatectomy
2009, Digestive and Liver Disease
Citation Excerpt :
Various factors implicated in liver failure after resection include resection-induced portal hypertension and shear stress damage to sinusoids [88–90], Pringle-induced impairment of liver regeneration [91] and endotoxin-mediated inhibition of proliferative pathways leading to hepatocyte apoptosis [92–95]. Cholestasis pre-operatively also has been observed to impair liver regeneration and function by restricting portal venous flow, inducing hepatocyte apoptosis and increasing translocation of gut bacteria [96–99]. Patient-related factors such as age and diabetes, may also adversely affect post-operative liver recovery [100,101].
Pre-operative determination of the risk of liver dysfunction has come under criticism with regards to its usefulness in clinical practice. Opinion is split between centres which use such tests uniformly on all patients and those where clinical judgment alone is used. Published data would not suggest any difference in mortality, morbidity or liver failure rates between these groups. This review outlines and presents the evidence for pre-operative quantification of functional liver remnant volume.
Cell cycle defects contribute to a block in hormone-induced mammary gland proliferation in CCAAT/enhancer-binding protein (C/EBPβ)-null mice
2005, Journal of Biological Chemistry
Citation Excerpt :
A well established model for studying cell cycle regulation in vivo is partial hepatectomy to study liver regeneration in rodents. Loss of C/EBPβ expression or decreased C/EBPβ activity in models of liver regeneration also have been associated with decreased levels of cyclin E, without detectable changes in cyclin D1 expression (35, 36). The conclusion from these studies is that C/EBPβ appears to control cyclin E expression, either directly or indirectly, in agreement with the present results with respect to hormone-induced mammary gland proliferation.
In contrast to hormone-dependent breast cancer, steroid hormone-induced proliferation in the normal mammary gland does not occur in the steroid-receptor positive cells but rather in adjacent cells via paracrine signaling involving several local growth factors. To help elucidate the mechanisms involved in the block in proliferation in hormone-receptor positive cells, we have utilized a CCAAT/enhancer binding protein (C/EBPβ)-null mouse model. Loss of this transcription factor results in increased steroid and prolactin receptor expression concomitant with a 10-fold decrease in proliferation in response to pregnancy hormones. To determine the basis for this decrease, several markers of cell cycle progression were analyzed in wild type and C/EBPβ-null mammary epithelial cells (MECs). These studies indicated that cell cycle progression in C/EBPβ-null MECs is blocked at the G₁/S transition. C/EBPβ-null mammary glands display substantially increased levels of the activated form of transforming growth factor β, a potent inhibitor of epithelial cell proliferation, as well as increased downstream Smad2 expression and signaling. While cyclin D1 levels were equivalent, cyclin E expression was markedly reduced in C/EBPβ-null as compared with wildtype MECs. In addition, increased p27 stability and retention in the nucleus and decreased levels of the cdc25a phosphatase contributed to a significant loss of cdk2 kinase activity. Collectively, these changes prevent C/EBPβ-null mammary epithelial cells from responding to hormone-induced proliferative signals.
Blockade of constitutively activated Janus kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human pancreatic cancer
2003, Cancer Letters
Constitutive activation of signal transducer and activator of transcription (Stat) proteins has been demonstrated in a wide variety of malignancies. In this study, we elucidated the significance of Janus kinase (JAK) and the downstream transcription factor Stat3 signals on malignant potentials of pancreatic cancer. Electrophoretic mobility shift assay and immunohistochemical analysis revealed that Stat3 was constitutively activated in subsets of human pancreatic cancer tissues and cell lines (Panc1, Kp4, AsPC-1, BxPC-3). A JAK-specific inhibitor, tyrphostin AG490, markedly inhibited Stat3 activation and expression of cyclin D1, bcl-xL and vascular endothelial growth factor mRNAs estimated by RT-PCR, as followed by growth arrest (6.3–21.3% vs controls; P<0.001) of pancreatic cancer cells. Inactivation of Stat3 by dominant-negative Stat3 adenovirus partly suppressed the growth of pancreatic cancer cells on day 4 post-inoculation (P<0.05) but not the expression of these mRNAs. These results indicate that activation of the JAK/Stat3 signaling pathway plays an important role in the progression of pancreatic cancer and that blockade of JAK/Stat3 signals may provide a novel therapeutic strategy for pancreatic cancer.
PPARγ ligand attenuates PDGF-induced mesangial cell proliferation: Role of MAP kinase
2003, Kidney International
Citation Excerpt :
Our results confirm the earlier observations of Law et al [32], who showed that the TZD analog troglitazone inhibits SRE function and reduces c-fos mRNA induction by basic FGF. C-fos and its heterodimeric partner c-jun (AP-1 complex) promote cell proliferation by transactivation of cyclin D1, a key protein promoting the cell cycle [9]. Cyclin D1 gene has been shown to harbor two AP-1 response elements in the promoter region [14] and is thus a potential target gene for AP-1 complexes.
PPARγ ligand attenuates PDGF-induced mesangial cell proliferation: Role of MAP kinase.
Mesangial proliferation is a key feature in the pathogenesis of a number of renal diseases and can be experimentally induced by the mitogen platelet-derived growth factor (PDGF). Mitogen-activated protein kinase (MAPK) signaling plays a key role in mesangial cell proliferation. In the present study we examined whether peroxisome proliferator-activated receptor gamma (PPARγ) activators/ligands, thiazolidinediones such as ciglitazone, troglitazone, and rosiglitazone, can inhibit cell proliferation by modulating individual steps in the MAPK pathway.
Mouse mesangial cells were made quiescent and proliferation was measured following the application of PDGF. Using ciglitazone as the model compound, the mechanism of the antiproliferative effect of PPARγ activators on MAPK and specific cell cycle regulatory proteins were examined by Western blot analysis and transfection studies.
Ciglitazone inhibited PDGF-induced mesangial cell proliferation in a dose-dependent manner (1 to 20 μmol/L). The inhibitory effect was blocked by a peroxisome proliferator-activated receptor element (PPRE) decoy oligonucleotide, indicating that the observed effect of ciglitazone was via PPARγ activation. Ciglitazone (1 to 20 μmol/L) did not affect extracellular signal-regulated protein kinase (ERK) activation but inhibited the activation of serum response element (SRE) by 85 ± 6% (P < 0.01). This effect was associated with a reduction in c-fos expression (80 ± 9%, P < 0.01). Ciglitazone (1, 10, and 20 μmol/L) also inhibited cyclin D1 expression by 37 ± 8%, 79 ± 15%, and 87 ± 12%, respectively (P < 0.001 to 0.001), and p21 expression by 45 ± 6% (P < 0.01), 61 ± 10% (P < 0.001), and 72 ± 8% (P < 0.001), respectively. Ciglitazone inhibited PDGF-mediated up-regulation of p27. In addition, the antiproliferative effect of ciglitazone was potentiated by PD98059, a mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor that acts at a step upstream from ERK.
These data indicate that PPARγ activation may inhibit mesangial growth directly by affecting MAPK and cell cycle regulatory proteins. Furthermore, a MAP kinase inhibitor can potentiate the antiproliferative effect.

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¹: To whom all correspondence should be addressed at Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. E-mail: [email protected] Fax: 81-92-642-5458.

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Biochemical and Biophysical Research Communications

Abstract

References (24)

Roles of CCAAT/enhancer-binding proteins in regulation of liver regenerative growth

J. Biol. Chemi.

Mouse JunD negatively regulates fibroblast growth and antagonizes transformation by ras

Cell

Liver regeneration

J. Hepatol.

Significance of blood ketone body ratio as an indicator of hepatic cellular energy status in jaundiced rabbits

Gastroenterology

Sequential changes of energy charge, lipoperoxide level, and DNA synthesis rate of the liver following biliary obstruction in rats

J. Surg. Res.

Sequential increases in the intrahepatic expression of epidermal growth factor, basic fibroblast growth factor, and transforming growth factor β in a bile duct ligated rat model of cirrhosis

Hepatology

Antioxidant-induced nuclear translocation of CCAAT/enhancer-binding protein β

J. Biol. Chem.

Disruption of the c/ebp alpha gene in adult mouse liver

Mol. Cell. Biol.

CCAAT/enhancer-binding protein α (C/EBPα) inhibits cell proliferation through the p21 (WAF-1/ CIP-1/ SDI-1) protein

Genes. Dev.

CCAAT enhancer- binding protein beta is required for normal hepatocyte proliferation in mice after partial hepatectomy

J. Clin. Invest.

Tumor necrosis factor-α induces c-jun during the regenerative response to liver injury

Am. J. Physiol.

Cited by (24)

Chapter 6 - Liver regeneration: Mechanisms and clinical relevance

Liver regeneration: Mechanisms and clinical relevance

Predicting liver failure following major hepatectomy

Cell cycle defects contribute to a block in hormone-induced mammary gland proliferation in CCAAT/enhancer-binding protein (C/EBPβ)-null mice

Blockade of constitutively activated Janus kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human pancreatic cancer

PPARγ ligand attenuates PDGF-induced mesangial cell proliferation: Role of MAP kinase

Regular ArticleLower Activity of CCAAT/Enhancer-Binding Protein and Expression of Cyclin E, but Not Cyclin D1, Activating Protein-1 and p21WAF1, after Partial Hepatectomy in Obstructive Jaundice

Abstract

J. Biol. Chemi.

Cell

J. Hepatol.

Gastroenterology

J. Surg. Res.

Hepatology

J. Biol. Chem.

Disruption of the c/ebp alpha gene in adult mouse liver

Mol. Cell. Biol.

CCAAT/enhancer-binding protein α (C/EBPα) inhibits cell proliferation through the p21 (WAF-1/ CIP-1/ SDI-1) protein

Genes. Dev.

CCAAT enhancer- binding protein beta is required for normal hepatocyte proliferation in mice after partial hepatectomy

J. Clin. Invest.

Tumor necrosis factor-α induces c-jun during the regenerative response to liver injury

Am. J. Physiol.

Regular Article
Lower Activity of CCAAT/Enhancer-Binding Protein and Expression of Cyclin E, but Not Cyclin D1, Activating Protein-1 and p21^WAF1, after Partial Hepatectomy in Obstructive Jaundice